Search

The normal soluble cellular prion protein, PrPC, is responsible for many cellular processes in our body. It gets structurally transformed into a misfolded, insoluble protein called PrPSc. This misfolded protein is responsible for a variety of neurodegenerative diseases commonly known as prion disease. The cause of this structural change from the alpha helical-rich structure of PrPC to the beta sheet-rich structure of PrPSc is not known yet. The PrPSc causes prion amyloids to form and aggregate at different parts of the brain, making it spongy in nature. In humans, prion disease is known by many names, including kuru, Gerstmann-Straussler-Scheinker disease, and Creutzfeldt Jakob disease (CJD). In sheep, it is known as scrapie and in cattle, it is mad cow disease or bovine spongiform encephalopathy (BSE). There are many treatment strategies to control prion disease, such as agents that can dissociate the prion amyloids, small molecules that can target the diseased prion and dissociate it, interfering RNAs, antiprion antibodies, and stem cell therapy. Stem cell therapy deals with the different types of differentiated stem cell grafts incorporation in scrapie-induced mice models. Stem cells from different origins such as neural stem cells (NSCs), embryonic stem cells (ESCs), adult stem cells, fetal neural stem cells (fNSCs), mesenchymal stem cells derived from bone marrow, etc., have been used as grafts to repair the damaged neural cells in the brain of prion-induced mice. Many results have been promising in improving the survival of mice, but very few could indicate a complete cure of the disease. Moreover, the time of disease onset and graft injection plays an important role in obtaining effective results. The strains of prion proteins most commonly used for infecting mice are Chandler, Obihiro, or RML, and the grafting is done well before the onset of disease symptoms to improve mice survival. In this chapter, we will discuss the different stem cell therapeutic approaches so far identified in managing prion disease.

The human prion diseases comprise Creutzfeldt–Jakob disease, variably protease-sensitive prionopathy, Gerstmann–Straussler–Scheinker disease, fatal familial insomnia, and kuru. Each is a uniformly fatal rare neurodegenerative disease in which conformational changes in the prion protein are thought to be the central pathophysiologic event. The majority of cases of human prion diseases occur worldwide in the form of sporadic Creutzfeldt–Jakob disease and a minority of around 10–15% are associated with mutations of the prion protein gene, termed PRNP, in the forms of genetic Creutzfeldt–Jakob disease, Gerstmann–Straussler–Scheinker disease, and fatal familial insomnia. Prion diseases are also transmissible and occur in iatrogenic and zoonotic forms (iatrogenic Creutzfeldt–Jakob disease and variant Creutzfeldt–Jakob disease respectively), adding a public health dimension to their management. Despite having a high public profile, human prion diseases are both rare and heterogeneous in their clinicopathologic phenotype, sometimes making a diagnosis challenging. A combined clinical, genetic, neuropathologic, and biochemical approach to diagnosis is therefore essential. The intensive study of these diseases continues to inform on neurodegenerative mechanisms and the role of protein misfolding in more common neurodegenerative diseases such as Parkinson disease and Alzheimer disease.

The first of several pivotal moments leading to current understanding of human transmissible spongiform encephalopathies (TSEs) occurred in 1959 when veterinary pathologist W.J. Hadlow first recognized several similarities between scrapie-a slow infection of sheep caused by an unusual infectious agent-and kuru, a fatal exotic neurodegenerative disease affecting only people of a single language group in the remote mountainous interior of New Guinea, described two years earlier by D.C. Gajdusek and V. Zigas. Based on the knowledge of scrapie, Gajdusek, C.J. Gibbs, Jr., and M.P. Alpers soon initiated efforts to transmit kuru by inoculating kuru brain tissue into non-human primates, that-although requiring several years-ultimately proved successful. In the same year that Hadlow first proposed that kuru and scrapie might have similar etiology, I. Klatzo noted that kuru's histopathology resembled that of Creutzfeldt-Jakob disease (CJD), another progressive fatal neurodegenerative disease of unknown etiology that A.M. Jakob had first described in 1921. Gajdusek and colleagues went on to demonstrate that not only the more common sporadic form of CJD but also familial CJD and a generally similar familial brain disease (Gerstmann-Straussler-Scheinker syndrome) were also transmissible, first to non-human primates and later to other animals. (Other investigators later transmitted an even rarer brain disease, fatal familial insomnia, to animals.) Iatrogenic CJD (spread by human pituitary-derived hormones and tissue grafts) was also transmitted to animals. Much later, in 1996, a new variant of CJD was attributed to human infection with the agent of bovine spongiform encephalopathy; vCJD itself caused an iatrogenic TSE spread by blood transfusion (and probably by a human-plasma-derived clotting factor). Starting in the 1930s, the scrapie agent was found to have a unique constellation of physical properties (marked resistance to inactivation by chemicals, heat and radiation), eventually interpreted as suggesting that it might be an unconventional self-replicating pathogen based on protein and containing no nucleic acid. The work of S.B. Prusiner led to the recognition in the early 1980s that a misfolded form of a ubiquitous normal host protein was usually if not always detectable in tissues containing TSE agents, greatly facilitating the diagnosis and TSEs and understanding their pathogenesis. Prusiner proposed that the TSE agent was likely to be composed partly if not entirely of the abnormal protein, for which he coined the term "prion" protein and "prion" for the agent. Expression of the prion protein by animals-while not essential for life-was later found to be obligatory to infect them with TSEs, and a variety of mutations in the protein clearly tracked with TSEs in families, explaining the autosomal dominant pattern of disease and confirming a central role for the protein in pathogenesis. Prusiner's terminology and the prion hypothesis came to be widely though not universally accepted. A popular corollary proposal, that prions arise by spontaneous misfolding of normal prion protein leading to sporadic cases of CJD, BSE, and scrapie, is more problematic and may serve to discourage continued search for environmental sources of exposure to TSE agents.

A number of virus-like agents have been discovered. These transmissible agents, including satellite viruses, viroids, and prions, are termed subviral agents, because they do not fit into the conventional definition of “virus” and they are smaller and simpler. A satellite virus possesses a particle structure indistinguishable from an ordinary virus, but it differs from a regular virus in that its propagation depends on another virus. Viroids, which are found only in plants, are constituted of “RNA only.” Conversely, prions, which are an etiologic agent of transmissible neurodegenerative diseases, are comprised of “protein only.” Unlike other infectious agents, a host-coded prion protein (PrP) solely constitutes the etiologic entity of prion diseases. In particular, PrP Sc , a misfolded aggregation-prone isoform of the cellular prion protein (PrP C ), is an infectious agent responsible for prion diseases.

Early genetic studies on scrapie, an infectious neurodegenerative disease of sheep that was adapted to mice, provided evidence in support of the hypothesis that the agent was a slow virus with a nucleic acid genome independent of the host. Particularly compelling support for an independent genome came from the existence of strains of scrapie agent, some of which were true breeding, while others appeared to mutate under selective pressure. Kuru, a neurodegenerative disease in the remote highlands of Papua New Guinea, had pathological changes similar to those in scrapie and also proved to be transmissible. Genetic studies with the tools of molecular biology and transgenic mice forced a reevaluation of earlier work and supported the prion hypothesis of a novel pathogen devoid of nucleic acid. In this chapter, I discuss the contributions of classical and molecular genetics to understanding PrP prion diseases and to determining that heritable information is enciphered in protein conformation.

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are invariably fatal neurodegenerative diseases of humans and animals. TSEs are believed to be caused by neuronal accumulation of a protease-resistant abnormal conformer of a host-encoded protein known as prion protein. One of the enigmatic properties of TSEs is that they could be both inherited and infectious. TSEs captured worldwide attention after bovine spongiform encephalopathy (BSE, also known as mad cow disease) emerged in Europe and spread to other animals and humans. Cross-species transmission of other animal TSEs was not as clearly documented although scrapie, a centuries-old TSE occurring in sheep, is believed to be the original source of the BSE outbreak.

Prion diseases or transmissible spongiform encephalopathies are neurodegenerative (non-inflammatory) diseases characterized by deposition in the CNS and some other organs of misfolded isoform of prion protein (PrPd). In humans, they include kuru, Creutzfeldt–Jakob disease (CJD), Gerstmann–Straussler–Scheinker disease, fatal familial insomnia, and variably protease-sensitive prionopathy. In animals, they include scrapie in sheep, goats, and mouflons; bovine spongiform encephalopathy; chronic wasting disease in cervids; and transmissible mink encephalopathy. The conversion of a normal cellular isoform of PrP into its misfolded pathological isoform PrPd underlies their pathogenesis. The concern is that other neurodegenerations, e.g. Alzheimer disease, Parkinson disease, tauopathies, and amyotrophic lateral sclerosis, in which misfolded proteins play a major role, may also exhibit prion-like properties. This chapter reviews the etiology, pathogenesis, molecular subtypes, and neuropathology of prion diseases, as well as the mutations causing hereditary forms of prion diseases. Sections on variant CJD and prionoids are also included.

In 1967, mathematician JS Griffiths postulated mechanisms by which a protein might function as a transmissible agent. In 1982, the term proteinaceous infectious particle (PrP, or the portmanteau ‘prion’ – to rhyme with virion) was introduced by Dr. Stanley Prusiner. A few years later, Charles Weissmann cloned the prion protein gene, leading to an apparent paradox not unlike that encountered in the early years of oncogene research; that is, what appeared at first to be an exogenously acquired infection actually lay dormant within each of us, presumably fulfilling some normal function. Thus were born the twin designations PrP c for the cellular form of the prion protein and PrP sc for the scrapie, or disease-causing, form of the protein, which appeared to differ only in secondary (and higher) structure. The development of antibodies capable of specifically recognizing PrP allowed the development of surrogate diagnostic tests based on immunologic detection of residual protease-resistant prion protein after partial proteinase K digestion. Prion diseases are unique in that they may occur as transmitted, genetic, or ‘sporadic’ (neither transmitted nor genetic) entities.

This chapter presents a historical perspective on the discovery of the simian immunodeficiency viruses (SIVs) that are ancestral to human immunodeficiency viruses (HIV-1 and HIV-2). The discovery of SIV and its recognition as a natural infection of African monkeys were made at National Institutes of Health (NIH) Primate Research Centers in the United States. The early misadventures of SIV research are recounted, including its detour, like HIV, through the delta-retrovirus family even though HIV was clearly recognized as a lentivirus. SIVmac (macaque), a pathogenic macaque virus, does not exist naturally. The story of how SIVmac was a manmade invention through the unintended consequences of kuru research is covered. Because SIV was first discovered in Asian macaques, its recognition as a nonpathogenic virus in African non-human primates came later from research on leprosy in sooty mangabeys, another serendipitous discovery. SIV research has generated over 6500 research publications and its impact has been far reaching, occupying the attention and resources of virtually every medical research institution, some governments, and tens of thousands of research scientists worldwide.

D. Carleton Gajdusek (1923–2008) was an American virologist and pediatrician who characterized the transmission of kuru, a spongiform encephalopathy found among the Fore people of New Guinea. He was jointly awarded the 1976 Nobel Prize for Physiology or Medicine with Baruch S. Blumberg; “for their discovery of new mechanisms for the origin and dissemination of infectious diseases”. He was jailed in 1997 for molesting children that he had brought from New Guinea and Micronesia and left the United States thereafter.

Prion diseases are rare in children. Three types are known: kuru, variant Creutzfeldt-Jakob disease (CJD), and iatrogenic CJD. All three affect children and young adults, and are transmitted by infectious contamination. Kuru was the result of ritual funeral practices similar to cannibalism; variant CJD affects young people who have eaten meat from cows with mad cow disease (mostly in the UK); and iatrogenic CJD is secondary to graft of human tissues performed in the 1980s (dura mater, pituitary extracted growth hormone). The disease appears after 4-30 years of incubation. The initial symptomatology is frequently neurological (cerebellar ataxia, oculomotor disturbance, peripheral nerve pain, pyramidal syndrome) followed by dementia. There is no biological test available that can give a definite diagnosis of prion disease apart from neuropathology, although prion accumulation in vCJD can be demonstrated in pharyngeal tonsil by immunohistochemical techniques. This devastating disease results inevitably in death. No specific treatment is available.

Publisher Summary The prion diseases are a related group of neurode­generative conditions that affect both humans and animals. The demonstration of transmission of prion disease by inoc­ulation of scrapie brain isolates into sheep, and of kuru, CJD and GSS brain isolates into primates, formed the basis for the concept of “transmissible dementias.” Human prion diseases encompass the three etiological types of prion disease including inherited, sporadic and acquired forms. Approximately, 15% of the human prion diseases are associ­ated with autosomal dominant pathogenic mutations in PRNP gene. Human prion diseases are associated with a range of clini­cal presentations and are classified by both clinicopathologi­cal syndrome and etiology, with subclassification according to the molecular criteria. All forms are invariably fatal following clinical onset; however, there is marked phenotypic variabil­ity depending upon etiology. Although the pathological consequences of prion infection occur in the central nervous system and experimental trans­mission of these diseases are most efficiently accomplished by intracerebral inoculation, most natural infections do not occur by these means.

Variant Creutzfeldt-Jakob disease, the human form of mad cow disease, triggered a health panic in the late twentieth century but it also greatly enhanced our understanding of prion diseases, a group of fatal transmissible spongiform encephalopathies that could be sporadic, familial or acquired by infection.

Tropical neurology began less than two centuries ago. Consumption of dietary toxins predominated at the beginning and gave birth to the geographic entity. The story moved from lathyrism through Jamaican neuropathy to cassava-induced epidemic neuropathy, which was contrasted with Konzo, also associated with cassava. Other tropical diseases enumerated with chronological details include: Chaga's diseases, kwashiorkor, Madras type of motor neuron disease, atlanto-axial dislocation, Burkitt's lymphoma and Kuru, associated with cannibalism among the Fore linguistic group in New Guinea. More recent documentation includes the Cuban neuropathy in 1991 with an epidemic of visual loss and neuropathy, Anaphe venata entomophagy in Nigeria presenting as seasonal ataxia, and neurological aspects of the human immunodeficiency virus infection complete the picture. With time, professional associations were formed and the pioneers were given prominence. The World Federation of Neurology featured Geographic Neurology as a theme in 1977 and Tropical Neurology was given prominence at its 1989 meeting in New Delhi, India. The situation remains unchanged with regards to rare diseases like Meniere's, multiple sclerosis, hereditary disorders. However, with westernization and continued urbanization, changing disease patterns are being observed and tropical neurology may depart from dietary toxins to more western world-type disorders.

Prion diseases are invariably fatal neurodegenerative diseases of humans and animals which attracted increased worldwide attention after detection of a bovine spongiform encephalopathy (BSE) outbreak and its transmission to humans causing variant Creutzfeldt–Jakob disease. Prion diseases are unique among other infectious diseases because of the unconventional characteristics of the etiologic agent and the biochemical mechanism for its propagation, and because of the sporadic, genetic, and transmissible nature of some of these diseases. The agent causing prion diseases, termed prion, is an abnormal conformer of a host-encoded cellular protein known as the prion protein. The fundamental event in the occurrence of prion diseases appears to be conversion of the cellular prion protein to the pathogenic prion by a poorly understood post-translational process. Transmission of prion diseases within the same species has been extensively documented. The modes of such transmissions include consumption of contaminated feed, accidental inoculation via medical or veterinary interventions, and close animal-to-animal contact. These transmissions result from exposures to secretions or tissues known to harbor the infectious agent, including the brain, spinal cord, and lymphatic tissues. Although cross-species spread of animal prion diseases has long been suspected, strong evidence for such spread is only available for the transmission of BSE to humans, domestic cats, and zoo animals.

© 2014 Elsevier Inc. All rights reserved.Prion diseases are biologically unique in that the infectious agent appears to be devoid of nucleic acid and consists of a post-translationally modified host protein. The recognition that variant Creutzfeldt-Jakob disease is caused by the same prion strain as bovine spongiform encephalopathy in cattle has dramatically highlighted the need for a precise understanding of the molecular biology of human prion diseases. The principles of protein conformation-based inheritance established from studying mammalian prions are of far wider relevance in human disease, and the emerging and rapidly developing field of protein-misfolding diseases has prion disease as a key paradigm.

Publisher Summary This chapter describes that prion diseases or transmissible spongiform encephalopathies are characterized by the deposition of PrPSc, an abnormal form of the normal cellular protein, PrPc. The unique nature of human prion diseases includes their pathogenesis, mode of transmission, and neuropathology. In humans, the disease is characterized by a long incubation time, rapid and dramatic evolution of the clinical disease course and an always lethal outcome. The chapter reviews the most common form of the human prion diseases, which is sporadic Creutzfeldt-Jakob disease (sCJD). It is generally regarded as a spontaneous neurodegenerative illness, arising either from a spontaneous PRNP somatic mutation or a stochastic PrP protein structural change. This disease form occurs worldwide and in each country with an epidemiological program. Increased numbers of cases of sCJD were reported after the implementation of active surveillance. The chapter explores the acquired forms of prion diseases that comprise kuru, iatrogenic CJD, and variant CJD. Modes of transmission are contact with human brain tissue and bovine spongiform encephalopathy in vCJD.

Publisher Summary Human transmissible spongiform encephalopathies (TSEs) or prion diseases represent a unique group of neuro-degenerative disorders that may be sporadic, infectious, or hereditary. Infectious forms of TSE may cause large out-breaks such as epidemics of kuru and variant Creutzfeldt-Jakob disease. Sporadic and hereditary forms of TSE are also found to be experimentally transmissible to non-human primates and rodents with similarly long incubation times. Recent advances in cellular and molecular biology have yielded increasingly strong evidence that TSE results from the accumulation in the brain of an abnormal isoform of prion protein, a post-translational modification of a normal host protein encoded by the PRNP gene. This abnormal isoform and its toxic fragments gradually accumulate in neurons resulting in neuronal death and other pathogenic effects that are responsible for the TSE phenotypes. Regular transmission of TSE to susceptible laboratory animals, including apes and monkeys, Syrian hamsters, and several strains of mice, is demonstrated in early TSE studies Also, transmission of kuru by cannibalistic rituals was experimentally confirmed by studies of alimentary transmission of TSE in Syrian hamsters by neuro-pathologic confirmation and establishing infectivity of their brain tissue.

Publisher Summary Transgenic technology has made an invaluable contribution to acquisition of new knowledge in prion biology, particularly in structural studies. Prion diseases are a group of rare transmissible neurodegenerative disorders that affect a range of mammalian species including humans. The human prion diseases have traditionally been classified into Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), and kuru. These rare diseases have recently attracted remarkable attention because of both their unique biology and concerns that the epidemic of the newly recognized bovine spongiform encephalopathy (BSE) could pose a threat to public health through dietary exposure to infected tissues.

Publisher Summary Prions are transmissible pathogens that cause fatal neurodegenerative diseases of the central nervous system in humans and animals. In humans, prion diseases have been subdivided into four classes and are referred to as kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), and fatal familial insomnia (FFI). These diseases can be sporadic, inherited, or infectious (or iatrogenic) disorders. They differ from other infectious diseases, in that the pathogen is a proteinaceous particle, termed a “prion,” and the essential component of prions is the scrapie prion protein (PrP Sc ).

Publisher Summary This chapter discusses the prion diseases that are fatal neurodegenerative disorders, which affect humans and animals. They represent a heterogeneous group that is unique among neurological diseases as it includes genetic, transmitted, and sporadic forms and displays a wide spectrum of clinical phenotypes and histopathological patterns. It is now evident that the prion protein (PrP) is central to the pathogenesis of these disorders whether inherited, infectious, or idiopathic (referred to as sporadic in the literature). In humans, prion diseases include Creutzfeldt–Jakob disease (CJD), Gerstmann–Straussler–Scheinker syndrome (GSS), kuru, fatal familial insomnia (FFI), and prion protein cerebral amyloid angiopathy (PrP–CAA). In animals, the most notable forms are scrapie in sheep and bovine spongiform encephalopathy in cattle. The sporadic, the infectious, and many of the genetically determined forms of human prion diseases, as well as the animal diseases, can be transmitted across and within animal species. Pathogenetically, they all appear to share a mechanism previously unrecognized, which differs from the established mechanisms of infectivity. The central principle involves the changes in conformation of the normal PrP that generate a pathogenic PrP conformer, which is capable of converting other normal PrP molecules into the abnormal form. This conversion results in degenerative cascade, and it has the potential to transmit the disease.

It is now well established that the transmissible subacute spongiform encephalopathies (TSE) are associated with an accumulation of pathological prion protein (PrPsc) that can be histologically observed under amyloid plaques formed in the brain parenchyma. These features constitute one of the characteristics of the TSE including scrapie in animals, and Kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, in humans. Although PrPsc copurifies with transmissible agent, the infectivity of the protein itself remains to be demonstrated. One enigmatic aspect of the PrPsc is its biogenesis. It has been established that PrPsc is an abnormal form of a cellular prion protein (PrPc), the gene of which is localized on chromosome 20 in humans. However, several unanswered questions concerning the mechanism of conversion and the intracellular site where it occurs, limit the full understanding of these mysterious diseases. In addition, knowledge of the exact localization of the normal isoform PrPc in brain cells constitutes an important challenge, not only to specify its transformation into PrPsc, but also to elucidate its role in neuronal cells. From studies demonstrating that PrPc, in the neuroblastoma cell line, is a constituent of the cell's surface membrane, it has been assumed that the protein plays a role in mechanisms involving intercellular communication. However, in the last three years, a set of data on various aspects of PrPc in neurons in vivo has permitted us to consider its involvement in neurotransmission. In this chapter, we review the main features of PrPc, and the evidence supporting the synapse as the privileged cellular site where the normal conformer of prion protein (PrPc), plays its physiological role. We also discuss the pathological consequences of this localization and similarities with other neurodegenerative disorders that target synapses.

Publisher Summary Kuru is one of the better-known paradigms of “place diseases,” or diseases occurring in high incidence in geographically restricted or delimited regions. From the study of kuru among the stone age fore in the Eastern Highlands of Papua, New Guinea, came the discovery of unconventional agents or slow viruses that cause neurodegenerative diseases in humans. In a similar fashion, the study of another place disease, a fulminating hematological malignancy in southwestern Japan, called adult T-cell leukemiailymphoma, led to the discovery of and etiological association with an exogenous replication-competent human retrovirus, human T-cell lymphotropic virus type I (HTLV-I). This initial frontier of HTLV-I research was expanded by the serendipitous discovery that endemic tropical spastic paraparesis, also known as Jamaican neuropathy and paraparesia espastica el Pucifico, another place disease in the Caribbean basin and Colombia, was also caused by HTLV-I. A clinically indistinguishable spastic myelopathy, designated HTLV-I-associated myelopathy, was later recognized among HTLV-I-seropositive individuals in southern Japan, and presently, HTLV-I-associated myelopathy and HTLV-I-positive tropical spastic paraparesis are considered to be the same disease. The study of diseases in populations isolated by the virtue of geography, culture, and/or genetics can also provide insights into the evolution and dissemination of the etiological agent. From the studies of HTLV-I infection in an isolated recently contacted group in the fringe highlands of Papua, New Guinea, and among the lifelong residents of the Solomon Islands has come an augmented perspective on the emergence, evolution, and global dissemination of this lymphotropic retrovirus. In addition, these studies in Melanesia have led to the realization that HTLV-I may, in certain instances, serve as a biological marker for the early and recent migrations of human populations.

Publisher Summary The bacterial infections can be grouped as typhoid fever, pneumococcal pneumonia, and meningococcal meningitis. Protozoal infections can be distinguished as amebiasis and malaria. There are the viral infections, such as influenza and hepatitis. And there are the nutritional deficiencies, such as scurvy, beriberi, and pellagra. The latest class of diseases to be discovered are the “slow virus diseases”—chronic progressive disorders with long incubation periods, caused by either conventional viruses, like that of measles, or by a newly defined group of “unconventional viruses,” which cause scrapie in sheep and kuru in man. The slow viral infections have certain puzzling characteristics. The diseases show an absence of inflammatory reaction or immunologic response. They are transmissible from host to host, but the nature of the transmitting agent is still cryptic. It appears to contain little or no nucleic acid, elicits no immune response, and resists the killing action of many common antibacterial and antiviral drugs.

Publisher Summary This chapter discusses the properties of the scrapie prion and its relationship to the infectious agents causing other apparently similar diseases. Six diseases are probably caused by prions, including scrapie, transmissible mink encephalopathy (TME), chronic wasting disease (CWD), kuru, Creutzfeldt–Jakob disease, and CJD, and Gerstmann–Straussler syndrome (GSS). Scrapie is a disease of sheep and goats. It is a neurological disorder characterized by pruritus, incoordination, and ataxia of gait. The disease is progressive and invariably fatal, as are all other prion diseases. A prolonged incubation period precedes the onset of clinical illness. The pathology of scrapie is confined to the central nervous system (CNS). Many countries have scrapie surveillance programs. Because sheep with scrapie cannot be treated, they are destroyed. The purification of the scrapie agent has been crucial for the studies defining the properties of the infectious particle. Several different purification procedures have been reported. One involved the copurification of the scrapie agent and microsomes. Another involved the isolation of a “membrane-free” fraction after prolonged ultracentrifugation. Multiple studies have shown that the scrapie agent in crude preparations is resistant to nuclease digestion and to UV irradiation.

Publisher Summary One of the most fascinating and perplexing areas of current biomedical research concerns the structure and biology of the unusual infectious particles causing scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. Over the last few years considerable progress has been made in unraveling some of the mysteries surrounding these novel infectious pathogens designated prions. Kuru, CJD, and Gerstmann-Straussler syndrome (GSS) are all transmissible neurodegenerative diseases of humans. The transmissibility of these three diseases to experimental animals has greatly facilitated studies concerning their etiology and pathogenesis. Like CJD, kuru and GSS also appear to be caused by prions. Three transmissible neurodegenerative diseases of animals are apparently caused by prions: scrapie of sheep and goats, transmissible mink encephalopathy (TME), and chronic wasting disease (CWD) of mule deer and elk.

Publisher Summary This chapter focuses on neurologic diseases of man with slow virus etiology. To date, two subacute degenerative diseases of the central nervous system of man, kuru and Creutzfeldt–Jakob disease (C-J), a presenile dementia of worldwide distribution with a basically similar lesion at the cellular level, have been shown to be caused by a very similar, very unconventional virus. Kuru is clinically characterized by cerebellar ataxia and a shivering-like tremor, which progresses to complete motor incapacity and death in about one year from onset. It has had a yearly incidence rate and prevalence ratio of about 1% of the population. During the early years of investigation, the disease was observed to affect all ages beyond infancy, being common in children of both sexes and in adult females, but rare in adult males. The Creutzfeldt–Jakob disease, one of the types of presenile dementias of man, has been successfully transmitted independently from 14 human cases to 18 chimpanzees. Incubation periods have ranged from 11 to 16 months, which is considerably shorter than those observed on primary transmission of kuru to chimpanzees.